The long-term objective of this study is to understand the role of cytotoxic T lymphocytes in the evolution of new human influenza A viruses and in protection against influenza virus infection. To accomplish this, a panel of murine cytotoxic T lymphocyte (CTL) clones specific for the hemagglutinin (HA) of an H3 human influenza A virus will be prepared. These clones will be analyzed in cytotoxicity assays for their ability (or inability) to recognize laboratory-selected and naturally-occurring variants with known HA sequences, tested for their capacity to select variants in vivo and in vitro, analyzed for the effect of class I MHC products on their specificity, and examine for their ability to reduce virus replication and mortality in mice infected with influenza viruses. These data will be used to: (1) determine the CTL recognition sites on the HA molecule: (2) evaluate the role of CTL in antigenic variation (drift and shift) in influenza viruses and the role of MHC restriction on the generation and specificity of HA-specific CTL; and (3) establish whether HA-specific CTL protect against morbidity and mortality in infected animals. Influenza A viruses produce major disease problems throughout the world and the role of CTL in the evolution of new epidemic strains has not been defined. A better understanding of this aspect of immunity may contribute to the future prevention of influenza and such information also has broader implications, vis-a-vis, the overall role of T cells in host defense.